Moscatilin inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating the WNT3/β-catenin signalling pathway

Tingting Zhang; Mengmeng Zhu; Jialing Ma; Zhenghong Liu; Zhidan Zhang; Meijie Chen; Yaping Zhao; Huaxin Li; Shengnan Wang; Xiaoning Wei; Wenwen Zhang; Xiaoxiao Yang; Peter J Little; Danielle Kamato; Hao Hu; Yajun Duan; Baotong Zhang; Jianbo Xiao; Suowen Xu; Yuanli Chen

doi:10.1016/j.jare.2024.02.020

Moscatilin inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating the WNT3/β-catenin signalling pathway

J Adv Res. 2024 Mar 2:S2090-1232(24)00082-1. doi: 10.1016/j.jare.2024.02.020. Online ahead of print.

Authors

Tingting Zhang¹, Mengmeng Zhu¹, Jialing Ma¹, Zhenghong Liu², Zhidan Zhang², Meijie Chen², Yaping Zhao², Huaxin Li¹, Shengnan Wang¹, Xiaoning Wei¹, Wenwen Zhang³, Xiaoxiao Yang¹, Peter J Little⁴, Danielle Kamato⁵, Hao Hu⁶, Yajun Duan⁶, Baotong Zhang⁷, Jianbo Xiao⁸, Suowen Xu⁹, Yuanli Chen¹⁰

Affiliations

¹ Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, School of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
² Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
³ Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China.
⁴ School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland 4102, Australia.
⁵ Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
⁶ Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
⁷ Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
⁸ Department of Analytical and Food Chemistry, Faculty of Sciences, Universidade de Vigo, Nutrition and Bromatology Group, Ourense, Spain.
⁹ Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Electronic address: sxu1984@ustc.edu.cn.
¹⁰ Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, School of Food and Biological Engineering, Hefei University of Technology, Hefei, China. Electronic address: chenyuanli@hfut.edu.cn.

PMID: 38432393
DOI: 10.1016/j.jare.2024.02.020

Abstract

Introduction: Vascular calcification, a devastating vascular complication accompanying atherosclerotic cardiovascular disease and chronic kidney disease, increases the incidence of adverse cardiovascular events and compromises the efficacy of vascular interventions. However, effective therapeutic drugs and treatments to delay or prevent vascular calcification are lacking.

Objectives: This study was designed to test the therapeutic effects and mechanism of Moscatilin (also known as dendrophenol) from Dendrobium huoshanense (an eminent traditional Chinese medicine) in suppressing vascular calcification in vitro, ex vivo and in vivo.

Methods: Male C57BL/6J mice (25-week-old) were subjected to nicotine and vitamin D₃ (VD₃) treatment to induce vascular calcification. In vitro, we established the cellular model of osteogenesis of human aortic smooth muscle cells (HASMCs) under phosphate conditions.

Results: By utilizing an in-house drug screening strategy, we identified Moscatilin as a new naturally-occurring chemical entity to reduce HASMC calcium accumulation. The protective effects of Moscatilin against vascular calcification were verified in cultured HASMCs. Unbiased transcriptional profiling analysis and cellular thermal shift assay suggested that Moscatilin suppresses vascular calcification via binding to interleukin 13 receptor subunit A2 (IL13RA2) and augmenting its expression. Furthermore, IL13RA2 was reduced during HASMC osteogenesis, thus promoting the secretion of inflammatory factors via STAT3. We further validated the participation of Moscatilin-inhibited vascular calcification by the classical WNT/β-catenin pathway, among which WNT3 played a key role in this process. Moscatilin mitigated the crosstalk between WNT3/β-catenin and IL13RA2/STAT3 to reduce osteogenic differentiation of HASMCs.

Conclusion: This study supports the potential of Moscatilin as a new naturally-occurring candidate drug for treating vascular calcification via regulating the IL13RA2/STAT3 and WNT3/β-catenin signalling pathways.

Keywords: Dendrophenol; IL13RΑ2; Moscatilin; STAT3; Vascular calcification; WNT3; β-catenin.